National Center for Emerging and Zoonotic Infectious Diseases

Dengue Vaccine 

Evidence to Recommendations Framework

Gabriela Paz Bailey, MD, PhD, MSc

Dengue Branch, Division of Vector-Borne Diseases, CDC

ACIP, June 24, 2021
2

Dengue

 DENV-1, 2, 3, 4 

o Lifelong DENV type-specific immunity

o Short-term cross-immunity 

 Transmitted by the Aedes mosquitoes

 Most frequent arboviral disease globally
Dengvaxia timeline

o 2015

o Trial results showed increased risk of severe disease among 2-5 year-olds

o 2016

o WHO position paper: 9y and older in highly endemic areas

o 2017

o Additional testing showed increased risk of severe dengue and hospitalization 

among vaccinated seronegative children compared to controls

o WHO revised their recommendations vaccine should only be given to children 

with laboratory-confirmed evidence of a past infection. 
FDA Licensing of first dengue vaccine 2019

For use in U.S. children 9-16 years old with laboratory-confirmed previous 

dengue virus infection and living in an area where dengue is endemic.
Test performance guidance for pre-vaccination 

screening 

98% specific

75% sensitive

90% positive predictive value

75% negative predictive value
Test Sensitivity % (95% CI) 

DENV

N=22

Specificity % (95% CI) 

NEG + ZIKV

N=85

ELISA test 2 68

(45, 86)

97

(90, 99)

Rapid test 3a 82

(60, 95)

98

(92, 100)

Rapid test 3b 68

(45, 86)

98

(92, 100)

Dr. Freddy Medina, CDC, personal communication

CDC evaluation of dengue virus IgG tests
Evidence to Recommendations Framework 
Evidence to Recommendations (EtR) Framework

EtR Domain Question

Public Health Problem • Is the problem (Dengue) of public health importance?

Benefits and Harms

• How substantial are the desirable anticipated effects of the intervention (dengue vaccine)?

• How substantial are the undesirable anticipated effects?

• Do the desirable effects outweigh the undesirable effects?

Values

• Does the target population feel the desirable effects are large relative to the 

undesirable effects?

• Is there important variability in how patients value the outcomes?

Acceptability • Is the intervention acceptable to key stakeholders?

Feasibility • Is the intervention feasible to implement?

Resource Use • Is the intervention a reasonable and efficient allocation of resources?

Equity • What would be the impact of the intervention on health equity?
Policy Question

Question: Should 3-doses of Dengvaxia be administered routinely to 

persons 9-16 years of age with laboratory-confirmed previous dengue 

infection and living in endemic areas?
Public Health Problem

Is dengue disease of public health importance?

○ No ○ Probably no ○ Probably yes ○ Yes ○ Varies ○ Don't know
Dengue endemic areas in the United States

85% of the children to be vaccinated are in Puerto Rico

Territory/Associated State Population 9-16 

years (2019) %

Puerto Rico 303,826 85%

US Virgin Islands 12,000 3%

American Samoa 10,100 3%

Federated States of Micronesia* 16,000 4%

Palau* 2,423 1%

Marshall Islands* 14,000 4%

*Sovereign freely associated states
95% of dengue cases in U.S. territories 

occur in Puerto Rico

0

500

1000

1500

2000

2500

2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

Number of Monthly Cases

Month of Symptom Onset

Puerto Rico American Samoa US Virgin Islands

Unusual period with little dengue transmission in PR

Source: Dengue cases in ArboNET, Jan 2010–May 2021. Case counts from 2020 and 2021 are preliminary and subject to change.
Dengue confirmed cases in Puerto Rico 

2020-2021

Source: Dengue passive surveillance system, Jan 2020–May 2021. Case counts from 2020 and 2021 are preliminary and subject to change. Reproduced with permission from Jomil Torres.
Dengue seroprevalence in Puerto Rico

• Argüello et al: 10-18 years1

• 2007 (n=345): 50% (95% CI: 44–56)

• Sanofi Pasteur trial data: 9-16 years2

• 2011 (n=152): 56% (95% CI: 47–64)

• COPA project3: 9-16 years, DENV PRNT>10

• 2018 (n=414): 59% (95% CI: 54–63)

1. Argüello DF, et al. AJTMH. 2015 Mar 4;92(3):486-91.

2. L’Azou M, et al. TRSTMH. 2018 Apr 1;112(4):158-68.

3. Unpublished.
Public Health Problem:

Work Group Interpretation

Is dengue disease of public health importance?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Benefits and Harms

How substantial are the desirable anticipated effects?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Efficacy virologically confirmed dengue (VCD) at 

25 months, seropositive participants 9-16 years

Hadinegoro SR et al. N Engl J Med 2015;373:1195-1206.
Efficacy against VCD by serotype, seropositive 

participants 9-16 years

Sridhar, S, et al. N Engl J Med. 2018 Jul 26; 379(4):327-340
Efficacy against hospitalization and severe dengue 

at 60 months, seropositive participants 9-16 years

Sridhar, S, et al. N Engl J Med. 2018 Jul 26; 379(4):327-340
Risk of dengue hospitalization for each time period 

over 6-years, seropositive participants 9–16 year

Forrat R et al. CID 2021.
How substantial are the desirable anticipated effects?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
How substantial are the undesirable anticipated effects?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Risk of hospitalization and severe dengue at 60 

months, seronegative participants 9-16 years

Sridhar, S, et al. N Engl J Med. 2018 Jul 26; 379(4):327-340
Severe adverse events and deaths among 

participants 9-16 years, serostatus combined 

Gustavo Dayan, Sanofi, personal communication.
Risk of dengue hospitalization for each time 

period over 6 years, seronegative participants 

ages 9–16 years 

Multiple imputation

Sanofi Pasteur, personal communication, March 15, 2021
How substantial are the undesirable anticipated 

effects?

○ Minimal ○ Small ○ Moderate ○ Large ○ Varies ○ Don't know
Do the desirable effects outweigh the undesirable 

effects?

o Favors 

intervention 

o Favors 

comparison 

o Favors 

both 

o Favors 

neither o Varies o Don't

know
Benefits and harms

• Benefits of Dengvaxia

• Efficacy against symptomatic virologically confirmed dengue (82%, CI: 67-90)

• Efficacy against dengue hospitalizations (79%, CI: 69-86)

• Efficacy against severe dengue (84%, CI: 63-93)

• Harms of Dengvaxia

• Increased risk of vaccine-induced hospitalization if a seronegative child is 

vaccinated after a false-positive laboratory test 
Population impact of screen and vaccinate 

strategy

• Agent-based model of dengue transmission with humans and mosquitoes 

represented as agents

• Calibrated to simulate dengue transmission in Puerto Rico

• Compares pre-vaccination screening and subsequent vaccination of 

seropositive 9-year-olds to the status quo

• Model population followed for 10 years keeping track of dengue infections, 

hospitalizations and deaths

• Prevalence at age 9 years of age of 50% and 30%

• Population level benefits: symptomatic and hospitalized cases averted 

• Risks: vaccine –induced hospitalizations among dengue-naïve individuals

Espana G, Leidner A, Waterman S, Perkins A. Cost-effectiveness of Dengue Vaccination in Puerto Rico. 

https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1
Population-level impacts of the intervention in Puerto Rico

Baseline Test and vaccinate 

strategy Averted Additional Ratio

Prior exposure 

in 9-yr-olds Symptomatic Hospitalizations Tested Vaccinated Symptomatic Hospitalizations Hospitalizations averted/additional

30% 221751 51278 317823 61825 1551 1262 112 11/1

50% 260218 60663 317814 102884 4148 2956 51 57/1

60% 271711 63807 317809 125127 5538 4295 28 152/1

Total numbers of symptomatic and hospitalized cases as well as cases averted and additional 

hospitalizations among vaccinees.

Time frame modeled: 10 years

Strategy: testing and vaccinating cohorts of test-positive 9-year-old children in Puerto Rico annually 

Test performance: sensitivity = 0.75 and specificity = 0.98.

Espana G, Leidner A, Waterman S, Perkins A. Cost-effectiveness of Dengue Vaccination in Puerto Rico. https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1

Sensitivity and specificity modified by Espana G. for this presentation.
51

2956

4148

0 1000 2000 3000 4000 5000

Vaccine-induced hospitalizations

Averted hospitalizations

Averted symptomatic

50% seroprevalence

Benefits and harms of vaccination among a 10-year cohort 

of 9-year-old children 50% seroprevalence

Screening test 75% sensitive and 98% specific

51 vaccine-induced hospitalizations in 

102,884 vaccinees (completed series)

Espana G, Leidner A, Waterman S, Perkins A. Cost-effectiveness of Dengue Vaccination in Puerto Rico. https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1

Sensitivity and specificity modified by Espana G. for this presentation.
Benefits and harms of vaccination among a 10-year cohort 

of 9-year-old children 30% seroprevalence

Screening test 75% sensitive and 98% specific

112

1262

1551

0 500 1000 1500 2000

Vaccine-induced hospitalizations

Averted hospitalizations

Averted symptomatic

30% seroprevalence

112 vaccine-induced hospitalizations in 61,825 

vaccinees (completed series)

Espana G, Leidner A, Waterman S, Perkins A. Cost-effectiveness of Dengue Vaccination in Puerto Rico. https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1

Sensitivity and specificity modified by Espana G. for this presentation,
50% seroprevalence

• Risks

• 51 vaccine-induced 

hospitalizations among 

seronegative children

• Benefits

• 4148 fewer symptomatic cases

• 2956 fewer hospitalizations

30% seroprevalence

• Risks

• 112 vaccine-induced 

hospitalizations among 

seronegative children

• Benefits

• 1551 fewer symptomatic cases

• 1262 fewer hospitalizations

Summary of population benefits and harms of vaccination 

among a 10-year cohort of 9-year-old children
Interpretation benefits and harms

• Shows positive balance for benefits versus harms

• Balance of risk and benefits varies by seroprevalence
Do the desirable effects outweigh the undesirable 

effects?

o Favors 

intervention 

o Favors 

comparison 

o Favors 

both 

o Favors 

neither o Varies o Don't

know
What is the overall certainty of the evidence?

Effectiveness of the intervention

○ 4 (very low) ○ 3 (low) ○ 2 (moderate) ○ 1 (high)

○ 4 (very low) ○ 3 (low) ○ 2 (moderate) ○ 1 (high)

Safety of the intervention
Values

Does the target population feel that the desirable 

effects are large relative to undesirable effects?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Is there important uncertainty about or variability in 

how much people value the main outcomes?

o Important 

uncertainty 

or variability

o Probably 

important 

uncertainty 

or variability

o Probably not 

important 

uncertainty 

or variability

o Not 

important 

uncertainty 

or variability

o No known 

undesirable 

outcomes
Acceptability

Is the intervention acceptable to key stakeholders?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Feasibility

Is the intervention feasible to implement?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Feasibility assessment has focused in PR due 

to burden, lessons learned will help prepare 

Territory/Associated State

Population 9-

16 years 

(2019)

% Vaccine 

providers Laboratories

Puerto Rico 303,826 85% 505 450

US Virgin Islands 12,000 3% 11 8

American Samoa 10,100 3% 4 1

Federated States of Micronesia* 16,000 4% 2 2

Palau* 2,423 1% 4 1

Marshall Islands* 14,000 4% 2 2

*Sovereign freely associated states
USVI survey of healthcare facilities (n=11)

• 4/11 were aware there was an FDA approved vaccine

• 5/11 would recommend the vaccine if there was a test available for 

screening

• 7/11 need more information before recommending it
Pacific Islands

• Presentation on Dengvaxia to PIHOA

• Planning a survey of providers by University of Georgia 

• Partnership to test left over samples of household-based surveys to 

determine dengue seroprevalence
Is the intervention feasible to implement?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Resource Use

Is the intervention a reasonable and efficient 

allocation of resources?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Cost-effectiveness analyses of Dengvaxia use in 

Puerto Rico 2019 Costs 

EtR Domain: ICER 50%: $122,000 per QALY Stakeholder sentiments

• Espana G, Leidner A, Waterman S, Perkins A. Cost-effectiveness of Dengue Vaccination in Puerto Rico. 

https://www.medrxiv.org/content/10.1101/2020.10.07.20208512v1

$11,000 per symptomatic $16,000 per hospitalization
Is the intervention a reasonable and efficient 

allocation of resources?

○ No ○ Probably no ○ Probably Yes ○ Yes ○ Varies ○ Don’t know
Equity

What would be the impact on health equity?

o Reduced o Probably 

reduced

o Probably no 

impact

o Probably 

increased o Increased o Varies o Don’t 

know
Balance of consequences

o Undesirable 

consequences 

clearly outweigh 

desirable 

consequences 

in most settings

o Undesirable 

consequences 

probably 

outweigh 

desirable 

consequences 

in most settings

o The balance 

between 

desirable and 

undesirable 

consequences is 

closely balanced 

or uncertain

o Desirable 

consequences 

probably 

outweigh 

undesirable 

consequences 

in most settings

o Desirable 

consequences 

clearly outweigh 

undesirable 

consequences 

in most settings

o There is 

insufficient 

evidence to 

determine the 

balance of 

consequences
Is there sufficient information to move forward with 

a recommendation?

○ Yes ○ No
Policy options for ACIP

o ACIP does not 

recommend the 

intervention (Intervention 

may be used within FDA 

licensed indications)

o ACIP recommends the 

intervention for individuals 

based on shared clinical 

decision-making

o ACIP recommends the 

intervention
Option 1: ACIP does not recommend

Cons

• A vaccine proven to protect persons with prior dengue infection will 

not be available to US citizens 

• Puts off making difficult decision that may be needed for the next 

dengue vaccine approved by FDA 

Pros

• Avoids a complicated implementation in the middle of COVID 

vaccinations programs
Option 2: Shared decision making

Cons

• Lower uptake

• Little progress in sorting out feasibility

• Coverage of test by insurance companies challenging

• May increase health inequities due to unequal health literacy

• Less buy-in for large scale education and communication

Pros

• Would lessen fears that the vaccine will become controversial and 

result in increased vaccine hesitancy
Option 3: Routine recommendation

Cons

• Public and media perception of the risks associated with the vaccine may increase vaccine hesitancy

• Potential public and provider perception that all hospitalizations among vaccinees related to vaccine

Pros

• Effective vaccine for seropositive children

• Greater coverage, reduction in hospitalizations 

• Better buy-in from health department and immunization program to resolve challenges with feasibility

• Broader communication and media campaign

• Increase in health equity
Policy options for ACIP consideration

o ACIP does not 

recommend the 

intervention (Intervention 

may be used within FDA 

licensed indications)

o ACIP recommends the 

intervention for individuals 

based on shared clinical 

decision-making

o ACIP recommends the 

intervention
Draft Recommendation

• ACIP recommends 3-doses of Dengvaxia administered 6 months apart 

at month 0, 6, and 12, in persons 9-16 years of age with a laboratory 

confirmation of previous dengue infection and living in endemic 

areas.
ACIP Dengue Vaccines Workgroup

ACIP Members

Kathy Poehling (Co-chair)

Wilbur Chen (Co-Chair)

Beth Bell

Veronica McNally

CDC Lead

Gabriela Paz-Bailey

Ex Officio Members 

Kaitlyn Morabito (NIH)

Ralph LeBlanc (FDA)

Kirk Prutzman (FDA)

Srihari Seshadri (DOD)

Liaison Representatives 

Elizabeth Barnett (AAP)

Rob Schechter (AIM)

Consultants

Edwin Asturias

Robert Atmar

Alan Barrett

Anna Durbin

Ines Esquilin

Tony Marfin

Hal Margolis

Kristen Pierce

Anita Shet 

Steve Waterman

CDC Contributors

Laura Adams

Josh Wong

Mimi Eckert

Rachel Eidex

Susan Hills

Terri Hyde

Mike McNeil

Jorge Munoz

Erin Staples

Cindy Weinbaum